Oxidative stress regulates IGF1R expression in vascular smooth-muscle cells via p53 and HDAC recruitment

Apoptosis of VSMCs (vascular smooth-muscle cells) leads to features of atherosclerotic plaque instability. We have demonstrated previously that plaque-derived VSMCs have reduced IGFI (insulin-like growth factor 1) signalling, resulting from a decrease in the expression of IGFI R (IGF I receptor) compared with normal aortic VSMCs [Patel, Zhang, Siddle, Soos, Goddard, Weissberg and Bennett (2001) Circ. Res. 88, 895-902]. In the present study, we show that apoptosis induced by oxidative stress is inhibited by ectopic expression of IGFIR. Oxidative stress repressed IGF1R expression at multiple levels, and this was also blocked by mutant p53. Oxidative stress also induced p53 phosphorylation and apoptosis in VSMCs. p53 negatively regulated IGFI R promoter activity and expression and, consistent with this, p53(-/-) VSMCs demonstrated increased IGF1R expression, both in vitro and in advanced atherosclerotic plaques in vivo. Oxidative-stress-induced interaction of endogenous p53 with TBP (TATA- box-binding protein) was dependent on p53 phosphorylation. Oxidative stress also increased the association of p53 with HDAC1 (histone deacetylase 1). Trichostatin A, a specific HDAC inhibitor, or p300 overexpression relieved the repression of IGFI R following oxidative stress. Furthermore, acetylated histone-4 association with the IGFIR promoter was reduced in cells subjected to oxidative stress. These results suggest that oxidative-stress-induced repression of IGFI R is mediated by the association of phosphorylated p53 with the IGFIR promoter via TBP, and by the subsequent recruitment of chromatin-modifying proteins, such as HDAC1, to the IGF1R promoter-TBP-p53 complex.